Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice

Endoplasmic reticulum (ER) stress is associated with increased reactive oxygen species (ROS), results from accumulation of misfolded/unfolded proteins, and can trigger apoptosis. ER stress is alleviated by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits protein translation allowing the ER to recover, thus promoting cell viability. We investigated whether osteoblastic cell apoptosis induced by glucocorticoids (GCs) is due to induction of ROS/ER stress and whether inhibition of eIF2α dephosphorylation promotes survival opposing the deleterious effects of GC in vitro and in vivo. Apoptosis of osteocytic MLO-Y4 and osteoblastic OB-6 cells induced by dexamethasone was abolished by ROS inhibitors. Like GC, the ER stress inducing agents brefeldin A and tunicamycin induced osteoblastic cell apoptosis. Salubrinal or guanabenz, specific inhibitors of eIF2α dephosphorylation, blocked apoptosis induced by either GC or ER stress inducers. Moreover, GC markedly decreased mineralization in OB-6 cells or primary osteoblasts; and salubrinal or guanabenz increased mineralization and prevented the inhibitory effect of GC. Furthermore, salubrinal (1 mg/kg/day) abolished osteoblast and osteocyte apoptosis in cancellous and cortical bone and partially prevented the loss of BMD at all sites and the decreased vertebral cancellous bone formation induced by treatment with prednisolone for 28 days (1.4 mg/kg/day). We conclude that part of the pro-apoptotic actions of GC on osteoblastic cells is mediated through ER stress, and that inhibition of eIF2α dephosphorylation protects from GC-induced apoptosis of osteoblasts and osteocytes in vitro and in vivo and from the deleterious effects of GC on the skeleton

Sonic Boom: Six Decades of Research

Sonic booms generated by aircraft traveling at supersonic speeds have been the subject of extensive aeronautics research for over 60 years. Hundreds of papers have been published that document the experimental and analytical research conducted during this time period. The purpose of this publication is to assess and summarize this work and establish the state-of-the-art for researchers just entering the field, or for those interested in a particular aspect of the subject. This publication consists of ten chapters that cover the experimental and analytical aspects of sonic boom generation, propagation and prediction with summary remarks provided at the end of each chapter. Aircraft maneuvers, sonic boom minimization, simulation techniques and devices as well as human, structural, and other responses to sonic booms are also discussed. The geometry and boom characteristics of various low-boom concepts, both large civil transports and smaller business-jet concepts, are included. The final chapter presents an assessment of civilian supersonic overland flight and highlights the need for continued research and a low-boom demonstrator vehicle. Summary remarks are provided at the end of each chapter. The studies referenced in this publication have been drawn from over 500 references

PTHrP-Derived Peptides Restore Bone Mass and Strength in Diabetic Mice: Additive Effect of Mechanical Loading

There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes mellitus (DM) and to develop therapeutic approaches to treat bone fragility in diabetic patients. We demonstrate herein that mice with type 1 DM induced by streptozotocin exhibited low bone mass, inferior mechanical and material properties, increased bone resorption, decreased bone formation, increased apoptosis of osteocytes, and increased expression of the osteocyte-derived bone formation inhibitor Sost/sclerostin. Further, short treatment of diabetic mice with parathyroid hormone related protein (PTHrP)-derived peptides corrected these changes to levels undistinguishable from non-diabetic mice. In addition, diabetic mice exhibited reduced bone formation in response to mechanical stimulation, which was corrected by treatment with the PTHrP peptides, and higher prevalence of apoptotic osteocytes, which was reduced by loading or by the PTHrP peptides alone and reversed by a combination of loading and PTHrP peptide treatment. In vitro experiments demonstrated that the PTHrP peptides or mechanical stimulation by fluid flow activated the survival kinases ERKs and induced nuclear translocation of the canonical Wnt signaling mediator β-catenin, and prevented the increase in osteocytic cell apoptosis induced by high glucose. Thus, PTHrP-derived peptides cross-talk with mechanical signaling pathways to reverse skeletal deterioration induced by DM in mice. These findings suggest a crucial role of osteocytes in the harmful effects of diabetes on bone and raise the possibility of targeting these cells as a novel approach to treat skeletal deterioration in diabetes. Moreover, our study suggests the potential therapeutic efficacy of combined pharmacological and mechanical stimuli to promote bone accrual and maintenance in diabetic subjects

New Pertussis Vaccination Strategies beyond Infancy: Recommendations by the Global Pertussis Initiative

Background. The Global Pertussis Initiative, an expert scientific forum, was established to address the ongoing problems associated with pertussis disease worldwide. Methods. The group analyzed pertussis disease trends, developed recommendations to improve disease control through expanded vaccination strategies, and proposed solutions to barriers to implementation and support of research activities. Results. Bordetella pertussis infection is endemic and continues to be a serious problem among unvaccinated or incompletely vaccinated infants. In addition, the reported incidence of pertussis disease is increasing in adolescents and adults, who not only experience a considerable health burden themselves but also infect vulnerable infants. Conclusions. Current vaccination strategies need to be reinforced. Expanded vaccination should include adding booster doses to existing childhood schedules (preschool or adolescent) and booster doses for those specific adult subgroups that have the highest risk of transmitting B. pertussis infection to infants (i.e., new parents, other contacts of newborns, and health care workers). More epidemiological studies and studies of disease transmission and the cost-effectiveness of vaccination would be valuable, and surveillance, diagnostic improvements, and educational campaigns are needed for implementation. However, as a prelude to universal adult vaccination, immediate universal adolescent vaccination should be instituted in countries in which it is economically feasibl

Superboom Caustic Analysis and Measurement Program (SCAMP) Final Report

The objectives of the Superboom Caustic Analysis and Measurement (SCAMP) Program were to develop and validate, via flight-test measurements, analytical models for sonic boom signatures in and around focal zones as they are expected to occur during commercial aircraft transition from subsonic to supersonic flight, and to apply these models to focus boom prediction of low-boom aircraft designs. The SCAMP program has successfully investigated sonic boom focusing both analytically and experimentally, while gathering a comprehensive empirical flight test and acoustic dataset, and developing a suite of focused sonic boom prediction tools. An experimental flight and acoustic measurement test was designed during the initial year of the SCAMP program, with execution of the SCAMP flight test occurring in May 2011. The current SCAMP team, led by Wyle, includes partners from the Boeing Company, Pennsylvania State University, Gulfstream Aerospace, Eagle Aeronautics, and Central Washington University. Numerous collaborators have also participated by supporting the experiment with human and equipment resources at their own expense. The experiment involved precision flight of a McDonnell Douglas (now Boeing) F-18B executing different maneuvers that created focused sonic booms. The maneuvers were designed to center on the flight regime expected for commercial supersonic aircraft transonic transition, and also span a range of caustic curvatures in order to provide a variety of conditions for code validations. The SCAMP experiment was designed to capture concurrent F-18B on-board flight instrumentation data, high-fidelity ground-based and airborne acoustic data, and surface and upper air meteorological data. Close coordination with NASA Dryden resulted in the development of new experimental instrumentation and techniques to facilitate the SCAMP flight-test execution, including the development of an F-18B Mach rate cockpit display, TG-14 powered glider in-flight sonic boom measurement instrumentation and "Where's the Focus?" (WTF) software for near-real time way-point computation accounting for local atmospherics. In May 2011, 13 F-18B flights were conducted during 5 flying days over a 2 week period. A densely populated 10,000 ft-long ground acoustic array with 125-ft microphone spacing was designed to capture pre-, focus, and post-focus regions. The ground-based acoustic array was placed in a nominally east-west orientation in the remote Cuddeback lakebed region, north of Edwards AFB. This area was carefully selected to avoid placing focused booms on populated areas or solar power facilities. For the SCAMP measurement campaign, approvals were obtained to temporarily extend the Black Mountain supersonic corridor northward by three miles. The SCAMP flight tests successfully captured 70 boom events, with 61 focus passes, and 9 calibration passes. Seventeen of the focus passes and three of the calibration passes were laterally offset; with the others being centerline flights. Airborne incoming sonic boom wave measurements were measured by the TG-14 for 10 of the F-18B flight passes including one maximum focus signature, several N-u combinations, several overlapped N-u signatures, and several evanescent waves. During the 27-month program, the SCAMP team developed a suite of integrated computer codes with sonic boom focusing predictive capabilities: PCBoom, Lossy Nonlinear Tricomi Equation Method (LNTE) and the Nonlinear Progressive wave Equation (NPE) method. PCBoom propagates the rays through the atmosphere and, in addition to legacy focus signature prediction based on the Gill-Seebass method, provides input source characteristics and propagation parameters to LNTE and NPE. LNTE, a Tricomi solver that incorporates atmospheric losses, computes the focus signature at the focus, and computes the focus signature in the vicinity of the focal zone, including the evanescent and post-focus zones. LNTE signature auralization from low-boom vehicle designs has been demonstrated in the NASA Langley Interior Effects Room (IER). The NPE has also been validated for use in prediction of focused ground boom signatures in sonic boom focal zones. The NPE formulation has the capability to incorporate atmospheric turbulence in the predictions. This has been applied to sonic boom propagation in the past. Prediction of turbulence effects on focal zone signatures was not, however, explored during the SCAMP program

Cooperativity and the origins of rapid, single-exponential kinetics in protein folding

The folding of naturally occurring, single domain proteins is usually well-described as a simple, single exponential process lacking significant trapped states. Here we further explore the hypothesis that the smooth energy landscape this implies, and the rapid kinetics it engenders, arises due to the extraordinary thermodynamic cooperativity of protein folding. Studying Miyazawa-Jernigan lattice polymers we find that, even under conditions where the folding energy landscape is relatively optimized (designed sequences folding at their temperature of maximum folding rate), the folding of protein-like heteropolymers is accelerated when their thermodynamic cooperativity enhanced by enhancing the non-additivity of their energy potentials. At lower temperatures, where kinetic traps presumably play a more significant role in defining folding rates, we observe still greater cooperativity-induced acceleration. Consistent with these observations, we find that the folding kinetics of our computational models more closely approximate single-exponential behavior as their cooperativity approaches optimal levels. These observations suggest that the rapid folding of naturally occurring proteins is, at least in part, consequences of their remarkably cooperative folding

Validation of Aircraft Noise Models at Lower Levels of Exposure

Noise levels around airports and airbases in the United States arc computed via the FAA's Integrated Noise Model (INM) or the Air Force's NOISEMAP (NMAP) program. These models were originally developed for use in the vicinity of airports, at distances which encompass a day night average sound level in decibels (Ldn) of 65 dB or higher. There is increasing interest in aircraft noise at larger distances from the airport. including en-route noise. To evaluate the applicability of INM and NMAP at larger distances, a measurement program was conducted at a major air carrier airport with monitoring sites located in areas exposed to an Ldn of 55 dB and higher. Automated Radar Terminal System (ARTS) radar tracking data were obtained to provide actual flight parameters and positive identification of aircraft. Flight operations were grouped according to aircraft type. stage length, straight versus curved flight tracks, and arrival versus departure. Sound exposure levels (SEL) were computed at monitoring locations, using the INM, and compared with measured values. While individual overflight SEL data was characterized by a high variance, analysis performed on an energy-averaging basis indicates that INM and similar models can be applied to regions exposed to an Ldn of 55 dB with no loss of reliability

Analysis of Acoustic Modeling and Sound Propagation in Aircraft Noise Prediction

An analysis has been performed of measured and predicted aircraft noise levels around Denver International Airport. A detailed examination was made of 90 straight-out departures that yielded good measurements on multiple monitors. Predictions were made with INM 5, INM 6 and the simulation model NMSIM. Predictions were consistently lower than measurements, less so for the simulation model than for the integrated models. Lateral directivity ("installation effect") patterns were seen which are consistent with other recent measurements. Atmospheric absorption was determined to be a significant factor in the underprediction. Calculations of atmospheric attenuation were made over a full year of upper air data at seven locations across the United States. It was found that temperature/humidity effects could cause variations of up to +/-4 dB, depending on season, for the sites examined. It was concluded that local temperature and humidity should be accounted for in aircraft noise modeling

N plus 3 Advanced Concept Studies for Supersonic Commercial Transport Aircraft Entering Service in the 2030-2035 Period

Boeing, with Pratt & Whitney, General Electric, Rolls-Royce, M4 Engineering, Wyle Laboratories and Georgia Institute of Technology, conducted a study of supersonic commercial aircraft concepts and enabling technologies for the year 2030-2035 timeframe. The work defined the market and environmental/regulatory conditions that could evolve by the 2030/35 time period, from which vehicle performance goals were derived. Relevant vehicle concepts and technologies are identified that are anticipated to meet these performance and environmental goals. A series of multidisciplinary analyses trade studies considering vehicle sizing, mission performance and environmental conformity determined the appropriate concepts. Combinations of enabling technologies and the required technology performance levels needed to meet the desired goals were identified. Several high priority technologies are described in detail, including roadmaps with risk assessments that outline objectives, key technology challenges, detailed tasks and schedules and demonstrations that need to be performed. A representative configuration is provided for reference purposes, along with associated performance estimates based on these key technologies